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- PDB-7ack: CDK2/cyclin A2 in complex with an imidazo[1,2-c]pyrimidin-5-one i... -

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Basic information

Entry
Database: PDB / ID: 7ack
TitleCDK2/cyclin A2 in complex with an imidazo[1,2-c]pyrimidin-5-one inhibitor
Components
  • Cyclin-A2
  • Cyclin-dependent kinase 2
KeywordsCELL CYCLE / cyclin-dependent kinase 2 / substituted imidazo[1 / 2-c]pyrimidin-5-one / inhibitor
Function / homology
Function and homology information


G2 Phase / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cyclin A2-CDK2 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / p53-Dependent G1 DNA Damage Response / mitotic cell cycle phase transition / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / Regulation of APC/C activators between G1/S and early anaphase ...G2 Phase / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cyclin A2-CDK2 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / p53-Dependent G1 DNA Damage Response / mitotic cell cycle phase transition / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / Regulation of APC/C activators between G1/S and early anaphase / cellular response to leptin stimulus / male pronucleus / Telomere Extension By Telomerase / G0 and Early G1 / female pronucleus / response to glucagon / cellular response to cocaine / cellular response to nitric oxide / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to insulin-like growth factor stimulus / positive regulation of DNA biosynthetic process / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / cochlea development / cellular response to platelet-derived growth factor stimulus / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / regulation of DNA replication / animal organ regeneration / post-translational protein modification / cellular response to estradiol stimulus / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / SCF(Skp2)-mediated degradation of p27/p21 / Orc1 removal from chromatin / G1/S transition of mitotic cell cycle / G2/M transition of mitotic cell cycle / positive regulation of fibroblast proliferation / Regulation of TP53 Degradation / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / Ub-specific processing proteases / protein domain specific binding / cell division / centrosome / DNA-templated transcription / positive regulation of DNA-templated transcription / protein kinase binding / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal ...Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal / Cyclin, N-terminal domain / Replication initiator protein RctB, central region / RctB, helix turn helix domain / Vibrionales, replication initiator protein RctB, central region / RctB helix turn helix domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / Protein kinase domain
Similarity search - Domain/homology
NITRATE ION / 8-cyclohexyl-6~{H}-imidazo[1,2-c]pyrimidin-5-one / Cyclin-A2 / Uncharacterized protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsSkerlova, J. / Pachl, P. / Rezacova, P.
Funding support Czech Republic, European Union, 3items
OrganizationGrant numberCountry
Ministry of Education (MoE, Czech Republic)Programme NPU I, project LO1304 Czech Republic
European Regional Development FundOP RDE No. CZ.02.1.01/0.0/0.0/16_019/0000729European Union
Grant Agency of the Czech Republic19-08410S Czech Republic
CitationJournal: Eur.J.Med.Chem. / Year: 2021
Title: Imidazo[1,2-c]pyrimidin-5(6H)-one inhibitors of CDK2: Synthesis, kinase inhibition and co-crystal structure.
Authors: Jansa, J. / Jorda, R. / Skerlova, J. / Pachl, P. / Perina, M. / Reznickova, E. / Heger, T. / Gucky, T. / Rezacova, P. / Lycka, A. / Krystof, V.
History
DepositionSep 11, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 24, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-dependent kinase 2
B: Cyclin-A2
C: Cyclin-dependent kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,82321
Polymers127,5364
Non-polymers1,28717
Water13,421745
1
A: Cyclin-dependent kinase 2
B: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,38110
Polymers63,7682
Non-polymers6138
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3990 Å2
ΔGint-9 kcal/mol
Surface area23310 Å2
2
C: Cyclin-dependent kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,44311
Polymers63,7682
Non-polymers6759
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4450 Å2
ΔGint-1 kcal/mol
Surface area23160 Å2
Unit cell
Length a, b, c (Å)71.305, 163.451, 73.190
Angle α, β, γ (deg.)90.000, 106.180, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 2 types, 4 molecules ACBD

#1: Protein Cyclin-dependent kinase 2 / Cell division protein kinase 2 / p33 protein kinase


Mass: 34143.547 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2, CDKN2 / Production host: Escherichia coli (E. coli) / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein Cyclin-A2 / Cyclin-A / Cyclin A


Mass: 29624.297 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNA2, CCN1, CCNA / Production host: Escherichia coli (E. coli) / References: UniProt: P20248

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Non-polymers , 5 types, 762 molecules

#3: Chemical ChemComp-R7B / 8-cyclohexyl-6~{H}-imidazo[1,2-c]pyrimidin-5-one


Mass: 217.267 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H15N3O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: NO3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 745 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.21 Å3/Da / Density % sol: 61.7 % / Description: Thin plate
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 10% w/v PEG 8000, 20% v/v ethylene glycol, 0.03 M sodium nitrate, 0.03 M disodium hydrogen phosphate, 0.03 M ammonium sulfate, and 0.1 M MOPS/HEPES-Na, pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 3, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.8→47.162 Å / Num. obs: 146615 / % possible obs: 98.5 % / Redundancy: 3.845 % / Biso Wilson estimate: 37.224 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.095 / Rrim(I) all: 0.111 / Χ2: 1.118 / Net I/σ(I): 9.7 / Num. measured all: 563689
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.8-1.913.8792.1250.69088123974234280.3142.46297.7
1.91-2.043.7160.9611.328230822609221470.6011.12298
2.04-2.23.9770.552.498257720956207650.8320.63599.1
2.2-2.413.8410.3124.257361019389191650.9320.36398.8
2.41-2.73.8490.1787.26646217484172670.9750.20698.8
2.7-3.113.8830.09612.745937415464152890.9930.11298.9
3.11-3.813.8270.04525.024955413096129490.9980.05298.9
3.81-5.363.7560.0336.74373471013499430.9990.03598.1
5.36-47.1623.8110.02441.9221576573156620.9990.02798.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XSCALEdata scaling
MOLREPphasing
REFMAC5.8.0158refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5lmk

5lmk


Resolution: 1.8→47.16 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.944 / SU B: 4.658 / SU ML: 0.124 / SU R Cruickshank DPI: 0.1086 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.109 / ESU R Free: 0.11 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2324 2100 1.4 %RANDOM
Rwork0.1969 ---
obs0.1974 144515 98.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 113.57 Å2 / Biso mean: 38.396 Å2 / Biso min: 20.3 Å2
Baniso -1Baniso -2Baniso -3
1-3.35 Å20 Å20.94 Å2
2---1.32 Å20 Å2
3----2.2 Å2
Refinement stepCycle: final / Resolution: 1.8→47.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8883 0 86 745 9714
Biso mean--46.55 45.1 -
Num. residues----1103
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0199211
X-RAY DIFFRACTIONr_bond_other_d0.0020.028765
X-RAY DIFFRACTIONr_angle_refined_deg1.5131.97712482
X-RAY DIFFRACTIONr_angle_other_deg0.9952.99520359
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.42751106
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.14523.959394
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.427151615
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7851545
X-RAY DIFFRACTIONr_chiral_restr0.0910.21408
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0219927
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021820
LS refinement shellResolution: 1.8→1.845 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.436 152 -
Rwork0.432 10432 -
obs--96.68 %

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